MECHANISM AND ROLE OF NOVEL CHLAMYDIAL TRANSCRIPTIONAL REGULATOR, CHXR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 衣原体是导致不孕不育、失明和肺炎的人类病原体，与心脏病密切相关，心脏病是人类的头号死因。衣原体是专性细胞内细菌，通过与发病密切相关的两个阶段的发育周期而永久存在。 发育周期主要是在转录水平上控制的；然而，我们对衣原体的发育调节机制的理解存在严重的缺陷。识别这些成分并确定其机制对于了解衣原体如何与宿主相互作用以及最终产生新的抗菌靶点至关重要。我们研究的长期目标是确定调控衣原体发育和发病的分子机制。这项建议旨在确定衣原体转录因子ChxR的结构和功能关系。中心假设是ChxR是衣原体发育及其毒力决定因素表达的主要调节因子。ChxR是一种26kD的蛋白，与研究广泛的OmpR反应调节亚家族同源。很大程度上是由于目前衣原体的遗传困难，ChxR的生物学作用尚不清楚。为了阐明ChxR的生物学作用并确定其调控机制，人们提出了以下具体目标：1)确定ChxR在体内的直接基因靶点；2)确定ChxR转录激活的机制；3)确定ChxR的三维结构。 作为这些研究的结果，我们预计将解决该领域的一个基本问题，即衣原体如何调节它们的生长？此外，由于像ChxR这样的反应调节因子在细菌中广泛存在，而在哺乳动物中不存在，它们是开发新抗菌剂的有吸引力的目标。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chlamydiae are human pathogens that cause sterility, blindness, and pneumonia, and are strongly correlated with heart disease, the number one cause of death in humans. Chlamydia are obligate intracellular bacteria and are perpetuated through a defining biphasic developmental cycle that is intimately linked with pathogenesis. The developmental cycle is governed predominately at the transcriptional level; however, there is a critical deficiency in our understanding of developmental regulatory mechanisms in Chlamydia. Identifying these components and characterizing the mechanisms is critical for understanding how Chlamydia interact with the host and eventual generation of novel antimicrobial targets. The long-term goal of our research is to characterize the molecular mechanisms that regulate chlamydial development and pathogenesis. This proposal is designed to determine the structural and functional relationships of a chlamydial transcription factor, ChxR. The central hypothesis is that ChxR is a master regulator of Chlamydia development and the expression of its virulence determinants. ChxR is a 26 kD protein homologous to the well-studied OmpR subfamily of response regulators. Largely due to the current genetic intractability of chlamydiae, the biological role of ChxR is not known. To elucidate the biological role and determine regulatory mechanism of ChxR the following specific aims are proposed: 1) define the direct in vivo gene targets of ChxR, 2) identify the mechanism of ChxR transcriptional activation, and 3) determine the three-dimensional structure of ChxR. As a result of these studies, we expect to address a fundamental question in the field, 'how do Chlamydia regulate their growth?' Furthermore, since response regulators like ChxR are widespread in bacteria and absent in mammals, they are attractive targets for development of new antimicrobials.